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1969
&CYANOETHYLATION OF PHENOXAZINE
metal had reacted. M70rk-up and distillation of the nitrogeneous material gave the following fractions: Fraction 1 2 3 4
B.P. (Mm.) 75-84 ( 2 . 5 ) 94-104 ( 2 . 5 ) 108-110 (2.5) Residue
ng 1.4624 1.4832 1.5010
Amount, G. 1.6 1.9 10.5 5.0
1699
Fraction 3 did not give classification tests for a carbonyl compound or a tertiary nitrogen atom. Permanganate oxidation" of a 5.0-g. sample of fraction 3 yielded picolinic acid, 1.2 g. (40% based on sample alone, 28.170 based on phenyl hexanoate), m.p. 135". Reported m.p. 133-134".11 Work-up of the neutral fraction gave phenol, 80.0 g.
LAFAYETTE, IND. (11) G. R. Clemo and G. R. Ramage, J . Chem. SOC.,440 (1931).
[CONTRIBUTION FROM T H E R A D I U M I N S T I T U T E O F THE UNIVERSITY O F P A R I S ]
Q-Cyanoethyla tion of Phenoxazine and 7H-Benzo[c]phenothiazine PAULETTE MVLLER, N. P. BUV-HOI, and R. RIPS Recaived June 15, 1959 Phenoxazine and 7H-benzo [c ]phenothiazine have been found to condense smoothly with acrylonitrile in the presence of organic alkaline catalysts; a-methylacrylonitrile failed to react. Friedel-Crafts cyclization of p-( 10-phenoxaziny1)propionic acid has been performed, and its reaction products are investigated.
From the triad formed by phenoxazine, phenothiazine, and phenoselenazine, the behavior of the last two in @cyanoethylation reactions has already been investigated, and both phenothiazine' and phenoselenazine2 were found to give the corresponding N-propionic acid in good yields. It is now shown that phenoxazine (I) likewise undergoes smooth P-cyanoethylation with acrylonitrile in the presence of benzyltrimethylammonium methoxide, to give p-(10-phenoxaziny1)propionitrile (11),the reaction being even more energetic than in the case of phenothiazine and phenoselen-
group and readily gave a phenylhydrazone. The higher-melting product, which did not form a phenylhydrazone in the same conditions, and which contained two atoms less of hydrogen, could be tentatively formulated as the dehydro derivative (V) of the former ketone. The differences in the degree of saturation of the two compounds are reflected in their infrared spectra (see Figure 1); in the case of ketone IS', the absorption band characterizing the ketone function is located a t 1655 cm.-', while for compound JTthere are two ketone bands, one a t 1630 cm.-' and the other a t 1640 cm. -I, a splitting resembling that observed with quinones. The infrared spectrum of ketone IV is similar to those of 2,3-dihydro-3-keto-lH-pyrido[3,2,1-kl]phenoselenazineand its 10-chloro- derivaH tive (see Figure 2). I In the framework of our investigations on poazine, probably because of its higher solubility in tential carcinogenic nitrogen-containing heteroacrylonitrile. I n similar and even more drastic cycles, the phenylhydrazones of ketone IV and of experimental conditions, a-methylacrylonitrile its analogs 2,3-dihydro-3-ke to- 1H-p yrido [3,2,1-kl ] failed to undergo condensation. Alkaline hydrolysis phenothiazine (VI; X = S) and 2,3-dihydro-3afforded P-(10-phenoxaziny1)propionic acid (111); keto-1H-pyrido [3,2,l-kl]phenoselenazine (T'I; X cyclization of this acid could be effected, as in the = Se) were converted by Fischer cyclizations into case of the corresponding propionic acids derived indolo [3',2'-2,3] - 1H-pyrido [3,2,1-kl]phenoxazine from phenothiazine' and phenoselenazine,2 with (T'II) and its phenothiazine and phenoselenazine phosphorus pentoside, but afforded two products, analogs (1-111)and (IX). The Pfitziiiger reaction of both of them yellow, the lower-melting one being ketone (1-1; X = S) with isatiri afforded 4'2,3 - dihydro - 3 - keto - 1H - pyrido[3,2,1 - kl]phenoxazine (I\'), as it possessed a reactive keto
I CH2-CH2-COzH I11
CH2J)CO CH, 1v
C H U C O CH
Y
(1) N. L. Smith, J. Org. Chem., 15, 1125 (1950). (2) P. Muller. 1. P. Buu-Hoi, and R. Rips, J . Orq. Chem., 24,37 (1959).
\'I
carboxyquinoleino [3',2'-2,3]- lH-pyrido[3,2,1- kl]phenothiazine (X; X = S), which underwent
1700
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MULLER, RIPS, AND BUU-HOi
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F R E OU E N C Y ( C M
-' )
1100
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24
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Fig. 1 - - - - compound IV compound V
decarboxylation to the base (XI). A similar reaction with the phenoselenazine ketone afforded 4'-
o;% o:%
"
'
H02C
\
I
~
\
I
XI
X
carboxyquinoleino[3',2' - 2,3] - 1H - pyrido [3,2,1kl]phenoselenazine (X; X = Se). I n the course of this work, 7H-benzo [clphenothiazine (XII) was also found to undergo ready &cyanoethylation, to give p-7- [7H-benzo [clpheno-
1
CH>-CH,-COIH XIV I
CH,-CH,--C3% XI11
thiazinyl]propionitrile (XIII) ; this compound underwent hydrolysis to the corresponding acid (XIV), whose cyclization will be discussed in a later paper. EXPERIMENTAL
0-( I0-PhenosazinyZ)propionztrile (11).To a mixture of 11 g. of phenoxazine and 15ml. of acrylonitrile 0.5 ml. of benzyltrimethylammonium methoxide was added dropwise with stirring, whereupon an exothermic reaction set up accom-
panied by a deep red coloration. The mixture was then heated on a water bath for 30 minutes, the acrylonitrile in excess w a ~distilled off in vacuo, and the solid residue taken up in benzene. The benzene solution was filtered, the solvent removed i n vamo, and the residue recrystallized from ether or ethanol, to form 33.5 g. of h e colorless needles, m.p. 123O, giving a red coloration in sulfuric acid. Anal. Calcd. for C16H12N10: C, 76.3; H, 5.1; N, 11.9. Found: C, 76.2; H, 5.4; N, 12.1. a-( 1O-PhenozazinyZ)pfoopionicacid (111).A solution of 6.8 g. of the foregoing nitrile and 7.5 g. of sodium hydroxide in 100 ml. of ethanol wa8 gently refluxed for 10 hr.; after cooling, water was added, and the solid precipitate of phenoxazine (m.p. 156") was filtered offby suction. The filtrate yielded on acidification with dilute hydrochloric acid, 5 g. of an acid, crystallizing from cyclohexane in shiny colorless needles, m.p. 138'. Anal. Calcd. for C1bH13S03:C, 70.5; H, 5.1; K, 5.5. Found: C, 70.8; H, 5.2; N, 5.6. Cyclization of 8-(IO-Phen0~azinyl)propionic acid (111). A solution of 3.5 g. of the above acid in 75 ml. of anhydrous benzene was refluxed for 1 hr. on a water bath with 19 g. of phosphorus pentoxide, and left overnight a t room temperature. The reaction mixture, which consisted by then of a brownish solid and a supernatant benzene phase, was carefully poured onto ice, the benzene solution was washed with aqueous sodium carbonate, then with water, and dried over sodium sulfate, and the solvent distilled off in vacuo. The yield was 2.7 g. of a solid which was dissolved in a mixture of benzene and cyclohexane; the less soluble portion conPisted of 0.5 g. of S-keto-1H-pyrido [S,d,l-kl]phenoxazine( V ) , bright yellow prisms which melted a t 228' after recrystallization from ethanol. This compound gave in sulfuric acid a tawny coloration which rapidly turned yellow. Anal. Calcd. for C1~HgN02: C, 76.6; €I, 3.8; 0, 13.6. Found: C, 76.5; H, 3.7; 0, 13.6. The mother liquors were concentrated, and furnished on cooling, 2 g. of 2,s-dihydro-9-keto-lH-pyrido [S,d,l-kl]phenoxazine (IV),which was recrystallized from ethanol to yield orange yellow prisms, m.p. 144", giving in sulfuric acid a deep blue coloration which turned yellow on heating. Anal. Calcd. for CI~HlliX02:C, 75.9; H, 4.6; 0, 13.5. Found: C, 75.8; H, 4.5;0, 13.5. The corresponding phenylhydrazone, prepared in ethanol,
NOVEMBER
19551
1701
P-CYANOETHYLATION OF PHENOXAZINE
I
1800
1700
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1400 1300 1200 FREQUENCY (C M-')
- _ - -compound (VI;
1100
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Fig. 2 X = Se)
IO-chloro derivative of compound (VI; X = Se)
crystallized from that solvent in pale yellow needles, m.p. 187", giving a red coloration in sulfuric acid. Anal. Calcd. for CP1Hl7NSO: N, 12.8. Found: N, 12.8. Indolo [3',2'-2,3]-1H-pyrido [3,1,1-kl]phenoxazine (VII). The Fischer cyclization of the foregoing phenylhydrazone (0.25 9.) was effected by boiling for a few minutes its solution in 5 ml. of acetic acid saturated with hydrogen chloride. After cooling, water was added, and the deep yellow precipitate (0.18 g.) was recrystallized from ethanol, giving yellow prisms melting above 300" and containing 1.5 moles of (Ithano1 (the analytical sample was dried for 30 minutes a t 160"). This compound gave in sulfuric acid a yellow halochromy with a green fluorescence. Anal. Calcd. for C21H14NJO:C, 81.3; H, 4.6; N, 9.0. Found: C, 81.0; H, 4.3; N, 9.0. Indolo [3',2'-2,3]-fH-pyrido[3,2,1-kl]phenothiazine (VIII). Similarly prepared from 2 g. of the phenylhydrazone of ketone (VI; X = S), this compound (1.5 9.) crystallized from ethanol in microscopic yellow needles, melting with decomposition a t 275" and containing crystallization solvent (the analytical sample xyas dried a t 160" as in the previous case). The halochromy in sulfuric acid was yellow. Anal. Calcd. for CzIH14N1S:C, 77.3; H, 4.3; N, 8.5. Found: C, 77.0; H, 4.6; N, 8.4. Indolo [3',2'-2,3]-1H-pyrido [3,2,l-kl]phenoselenazine(IX). Prepared as for the above from 0.3 g. of the phenylhydrazone of ketone (VI; X = Se), this indole (0.2 g.) crystallized from ethanol in yellow needles, m.p. 258", giving a yellow halochromy in sulfuric acid. Anal. Calcd. for C2,H14N2Se: S , 7.8. Found: K, 7.7. 4'-Carboxyquinoleino [3',,5"-2,3]-1H-py~ido [S,%,l-kllphenothiazine (X; X = S). A mixture of 2.5 g. of ketone (VI; X = S), 1.5 g. of isatin, and 1.7 g. of potassium hydroxide in 10 ml. of ethanol was refluxed for 40 hr.; after cooling, water was added, and the yellow potassium salt of the cinchoninic acid obtained was filtered off, suspended in water, and the free acid liberated by addition of acetic acid. Yield: 2.7 g. of reddish-brown microcrystals, m.p. 325", giving a green coloration in sulfuric acid. Anal. Calcd. for CZ1H,,N2O2S:2r;, 7.4; S, 8.4. Found: N, 7.1; S, 8.1. Quinoleino [S',Bf-2,S]-1H-pyrido [3,b,l-kl]phenothiazine ( X I ) , prepared by thermal decarboxylation of the foregoing acid, crystallized from ethanol in yellow prisms, m.p. 202O.
Anal. Calcd. for C2,Hl4N2S:N, 8.3; S, 9.5. Found: K, 8.3; S, 9.2. 4'-Carboxyquinoleino [3',2'-2,3]-1H-pyrido [3,2,1-kl Iphenoselenazine (X; X = Se). Prepared and purified as for the sulfur analog, this acid crystallized from ethanol in brownish needles, melting with decomposition above 300°, and giving a dark green halochromy in sulfiiric acid. Anal. Calcd. for CZ3Hl4N2O2Se: C, 64.3; H, 3.3. Found: C, 64.0; H, 3.3. 6-7'- [YH-Benzo [c]phsnothtazinyZ]propionitriZe(XTII). To a suspension of 15.5 g. of 7H-benzo[c]phenothiazine ( X I I ; prepared from N-phenyl-P-naphthylamine and sulfur in the presence of iodinea; the product was purified by distillation in vacuo: b.p. 235-240"/0.1 mm., m.p. 178') in 25 ml. of acrylonitrile, 1 ml. of benzyltrimethylammonium methoxide was added dropwise, and the mixture heated for 30 minutes on a water bath. The paste obtained was left overnight a t room temperature; the reaction product was then taken up in 250 ml. of hot benzene, the solvent was removed, and the residue recrystallized from acetone, to furnish 12 g. of colorless needles, m.p. 224", giving a deep blue halochromy in sulfuric acid. Anal. Calcd. for ClsH14N2S:C, 75.5; H, 4.7; X, 9.3. Found: C, 75.5; H, 5.0; N, 9.4. 6-7- [TH-benzo [c]phenothiazinyl]propionic acid (XIV). A suspension of 5.5 g. of the foregoing nitrile in 100 ml. of a 5y0 solution of sodium hydroxide in ethanol was refluxed for 10 hr.; after cooling, 200 ml. of water was added, and the precipitate of 7H-benzo [clphenothiazine ( 2 g.) was filtered off. The filtrate yielded on acidification with dilute hydrochloric acid, 3.3 g. of a solid acid, crystallizing from ethanol in fine colorless needles, m.p. 190". The halochromy in sulfuric acid was deep blue. Anal. Calcd. for CIYHl5NO2S:C, 71.0; H, 4.7; S , 4.4. Found: C, 71.0; H, 5.0; N, 4.1.
Acknowledgment. We thank Eastman Chemical Products Inc. (Kingsport, Tennessee) for the amethylacrylonitrile used in this work. PARIS VE, FRANCE (3) E. Knoevenagel, J . prakt. Chem., [Z]89, 17 (1914).
